Abstract
As classical agonists for peroxisomal proliferator-activated receptor alpha (PPARα), fibrates activate renal fatty acid metabolism (FAM) and provide renoprotection. However, fibrate prescription is limited in patients with kidney disease, since impaired urinary excretion of the drug causes serious adverse effects. Pemafibrate (PEM), a novel selective PPARα modulator, is mainly excreted in bile, and, thus, may be safe and effective in kidney disease patients. It remains unclear, however, whether PEM actually exhibits renoprotective properties. We investigated this issue using mice with fatty acid overload nephropathy (FAON). PEM (0.5 mg/kg body weight/day) or a vehicle was administered for 20 days to 13-week-old wild-type male mice, which were simultaneously injected with free fatty acid (FFA)-binding bovine serum albumin from day 7 to day 20 to induce FAON. All mice were sacrificed on day 20 for assessment of the renoprotective effect of PEM against FAON. PEM significantly attenuated the histological findings of tubular injury caused by FAON, increased the renal expressions of mRNA and proteins related to FAM, and decreased renal FFA content and oxidative stress. Taken together, PEM exhibits renoprotective effects through the activation and maintenance of renal FAM and represents a promising drug for kidney disease.
Highlights
Peroxisomal proliferator-activated receptor α (PPARα) is a member of the steroid/nuclear receptor superfamily
The renal expressions of mRNA and proteins related to fatty acid metabolism (FAM) were significantly enhanced in the PEM group as compared with the Veh group (Figure 1)
FAM in peroxisomes, i.e., L-peroxisomal bifunctional protein (PH) and peroxisomal 3-ketoacyl-CoA thiolase (PT), were markedly increased. These results indicated that PEM improved lipid metabolism and activated renal FAM without obvious adverse effects
Summary
Peroxisomal proliferator-activated receptor α (PPARα) is a member of the steroid/nuclear receptor superfamily. FAM deficiency causes excess lipid accumulation in PTECs, further kidney injury, and the progression of renal dysfunction through lipotoxicity (LTx) [5]. Based on these facts, the activation of PPARα signaling and FAM in the kidney is presumed to suppress renal fibrosis and the progression of renal dysfunction in patients with chronic kidney disease (CKD) [6]. Pemafibrate (PEM) was first approved in Japan in 2017 This novel drug is pharmacologically defined as a selective PPARα modulator (SPPARMα), with a mode of PPARα activation different from those of classical fibrates. PEM is considered safe and efficient for kidney disease, it remains unclear whether it can exert renoprotective effects. We administered PEM to fatty acid overload nephropathy (FAON) model mice and assessed its protective properties in the kidney
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